Fragile X messenger ribonucleoprotein 1-217 mis-spliced RNA isoform (FMR1-217)

FMR1-217 is an aberrant, mis-spliced RNA isoform of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, resulting from the inclusion of a cryptic pseudo-exon located in intron 1. This isoform is produced in a CGG expansion-dependent manner and is prevalent in approximately 70% of individuals with Fragile X Syndrome (FXS), as well as in some premutation carriers (Shah et al., 2023; PNAS). The inclusion of the pseudo-exon leads to a truncated transcript that fails to produce functional FMRP protein, a critical regulator of synaptic translation and brain development (QurAlis, 2025; UMass Chan). Therapeutic strategies involve using splice-switching antisense oligonucleotides (ASOs) to mask the pseudo-exon, which redirects the splicing machinery to produce full-length, functional FMR1 mRNA (FRAXA, 2025). This mechanism offers a novel precision medicine approach to restore endogenous FMRP levels in patients who were previously thought to have completely silenced FMR1 genes. Additionally, FMR1-217 serves as a potential biomarker, as it is detectable in the blood and cerebrospinal fluid of affected individuals (ScienceDaily, 2023).

Other names

FMR1-217 RNAFMR1-217 transcriptFMR1 pseudo-exon 1 isoformMis-spliced FMR1 isoformENST00000621447.1

Splice-switching antisense oligonucleotides (ASOs) bind to the cryptic splice sites or the pseudo-exon within the FMR1 pre-mRNA to block its inclusion, thereby restoring the canonical splicing of full-length FMR1 mRNA and subsequent translation of functional FMRP protein.